Two primary clinical deficits associated with Spinal Cord Injury (SCI) are spastic muscle "hypertonia" and impaired voluntary control of movement. Hypertonia, defined as an abnormal increase in muscle tone, is a defining feature of spasticity and has both diagnostic and therapeutic significance. Hypertonia arises from abnormalities in mechanical properties of muscles, passive tissues, and reflexes. Various physical and pharmacological treatments have been proposed to decrease hypertonia and to improve function. However, the effects of such interventions have not been quantified, primarily due to a lack of quantitative tools that can separate and characterize these components. To address this deficit, we have developed a "parallel cascade" system identification model that can be used to characterize joint dynamic stiffness and separate its muscular and reflexive components. The overall goal of this study is to predict the effects of therapeutic interventions on functional recovery. We plan two interventions;a pharmacological intervention (tizanidine, the 1-2 noradrenergic agonist), and a physical intervention (robotic locomotor training [LOKOMAT]). Although tizanidine has been used to treat spasticity, and the LOKOMAT to improve locomotion, there have been no prior attempts to characterize the interactions between these therapies. The focus of this study will be on the mechanisms of action of these interventions in SCI. Therefore, we plan to quantify the effects of these interventions on neuromechanical abnormalities associated with spasticity and on impaired voluntary movement and functional impairment, in addition to determining the relationship between these two. Aim 1 is to determine the effect of tizanidine and the LOKOMAT on voluntary and reflexive motor behavior by using the parallel system identification technique to characterize the impact of these interventions on reflex and mechanical properties associated with spasticity. We hypothesize that tizanidine and the LOKOMAT will each modify reflex function and muscle mechanics;however, combining these techniques will improve outcomes over each intervention separately. Aim 2 is to quantify the effects of these treatments on impaired voluntary movement. We hypothesize that tizanidine will improve active range of motion, movement smoothness and movement time. The LOKOMAT will improve maximum speed, active range of motion and movement time. Furthermore, combined tizanidine and LOKOMAT will improve all these movement parameters to a disproportionate extent. Aim 3 is to quantify the effects of these treatments on clinical measure of impairments and functional limitations. We hypothesize that tizanidine will improve, muscle strength, gait endurance and volitional control. The LOKOMAT will improve passive range of motion, muscle strength, gait speed and endurance, balance, and ambulation. We expect to see even greater improvements when the two interventions are combined. Aim 4 is to determine the contributions of changes in neuromuscular properties to improvement in impaired voluntary movement, clinical impairments and functional impairments. The results will document the role of each mechanical abnormality in functional impairments for each treatment. We hypothesize that the reduced reflex stiffness, as well as the modified muscle mechanics, will be related with improvement of the movement parameters, gait endurance and speed, volitional control, and ambulation. Our results will provide the information needed to develop accurate, quantitative models, capable of distinguishing changes in muscular system from changes in neural pathways in neurological disorders such as SCI. We should also be able to analyze their contributions to functional impairment. Improved understanding of the role of muscular and reflexive abnormalities in impaired movements, combined with accurate assessment techniques, will enable us to predict the outcome of various clinical interventions, and consequently to prescribe optimal treatment for spasticity and impaired walking. PUBLIC HEALTH RELEVANCE: There are approximately 200,000 cases of spinal cord injury (SCI) in the U.S., and that number increases by 10,000 each year. About half of these individuals have incomplete motor injuries that usually result in impaired voluntary muscle activation, increased fatigue, and spasticity. Spasticity associated with this injury includes exaggerated stretch reflexes and involuntary muscle spasms that disrupt daily activity, shorten life span, and have physical, emotional and social costs. An effective treatment of spasticity and movement impairments could, therefore, have many benefits. We plan to show that, in individuals with incomplete SCI injuries, specific medications have the potential to alter neuromuscular function and behavior when combined with physical interventions. The overall goal is to use novel biomechanical models to predict the effects of these specific interventions on functional recovery in patients with incomplete SCI to optimize the treatments. The first specific goal is to determine, by using a novel technique, the effects of combining drug therapy with robotic locomotor training. The second specific goal is to measure the effects of these treatments on impaired voluntary movements. The third goal is to assess the effects of these treatments with a clinical measure of impairments and functional limitations. Finally, the fourth specific goal is to find the contributions of improved muscular and reflexive properties resulting from these therapeutic interventions, to improving voluntary movement and reducing functional limitations. We hypothesize that the drug therapy may improve reflexive behavior, active range of motion and voluntary control and gait endurance. The physical intervention may improve reflexive and muscular function, impaired voluntary movement, gait speed and endurance, balance and locomotion. Further, combined physical and pharmacological interventions may improve all of these impairments and functional limitations to a greater degree than either intervention alone. The results will document the effect of each mechanical abnormality on impaired movement and function, for each treatment. This may lead to better understanding of the mechanisms of action of these interventions, and for improving treatments.